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Ever think about Round #2 of Iressa after first fails???


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CORONADO, Calif. -- Non-small cell lung cancer may respond to a second round of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment even when the first failed, researchers found.

In an 18-patient study, gefitinib (Iressa) retreatment after chemotherapy yielded a disease control rate of 80.0%, reported In-Jae Oh, MD, PhD, of Chonnam National University Hwasun Hospital in Gwangju, South Korea, and colleagues.

Among six evaluable patients who had an initial partial remission to the EGFR-targeted therapy, two had a partial response again with the second attempt.

Two patients had an even better response to the second round of gefitinib than on the first, the researchers reported here at the Joint Conference on Molecular Origins of Lung Cancer.

Among the nine evaluable patients in the cohort with stable disease initially on gefitinib, two had a partial remission on retreatment.

"Intratumor heterogeneity may be an answer," the researchers told attendees at the conference, which was sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

The researchers noted that acquired resistance to EGFR tyrosine kinase inhibitors largely stems from a mutation called T790M (50%) or from C-met amplification (15%), but that at least 40% become resistant for unknown reasons.

Oh's group proposed that tumors originally comprised of a mix of EGFR-dependent and EGFR-independent cells may have an initial response as the EGFR-dependent cells are killed off by targeted therapy.

The EGFR-independent tumor cells that eventually cause progression may be substantially killed off by chemotherapy.

Progression after chemotherapy is then largely due to regrowth of EGFR-dependent cells, which can again respond to EGFR-based therapy, Oh and colleagues postulated as one explanation.

"People fail for different reasons," noted Roy Herbst, MD, PhD, of the M.D. Anderson Cancer Center in Houston.

While this small phase II study needs more confirmation, the approach is appealing, said Herbst, a conference co-chair.

"There are not very many options for patients that have failed erlotinib [Tarceva] and chemotherapy," he told MedPage Today. "So people are trying retreatment. This may provide more impetus for that."

The similarity between gefitnib and erlotinib molecules suggests that the findings would generalize to erlotinib as well, Herbst said.

Oh's study included 18 non-small cell lung cancer patients who had initial control of disease on gefitinib (38.9% partial response by RECIST criteria, 61.1% stable disease).

After disease progression, all went on to at least one cycle of chemotherapy but again had progression of advanced or metastatic non-small cell lung cancer.

Gefitinib was reintroduced, but three patients could not be evaluated by chest CT imaging for response to this treatment due to death or other drop out.

Gefitinib retreatment lasted for a median of 85.5 days compared with the 263.5-day median on initial treatment.

The results of retreatment with gefitinib among the 15 evaluable patients were:

* An overall disease control rate of 80.0% with partial remission achieved by 26.7% and stable disease in 53.3%

* Disease control in 83.3% who had a prior partial remission on the EGFR-targeted drug (two partial remissions, three stable disease, one disease progression)

* Disease control in 77.8% of patients who previously achieved stable disease on gefitinib (two partial remissions, five stable disease, two disease progressions)

Paul A. Bunn, Jr., MD, of the University of Colorado Denver, who commented on the study at a press conference, said that this approach is currently his standard of care for treatment failures.

While most patients currently go on to chemotherapy after initial failure of an EGFR tyrosine kinase inhibitor, one prior study has shown benefits to simply reintroducing the drug without intervening chemotherapy, Bunn said.

Another possibility would be to give erlotinib or gefitinib plus a new targeted therapy, Herbst said. "I think that's where this study leads."

The researchers provided no information on conflicts of interest.

Herbst reported no relevant conflicts of interest. Bunn reported having consulted for OSI pharmaceuticals and Genentech.

Primary source: American Association for Cancer Research-International Association for the Study of Lung Cancer

Source reference:

Oh I-J, et al "Retreatment of Gefitinib in the patients with non-small cell lung cancer (NSCLC) previously responded to Gefitinib: A single arm, open label, phase II study" AACR-IASLC 2010; Abstract B24.

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